The field of this invention relates to mineralized coatings of prosthetic devices. More particularly the invention relates to a porous calcium phosphate mineral coated prosthesis which includes a coating having a therapeutic agent, such as an antibiotic in water, absorbed therein.
The use of prosthetic devices for treatment of bone injuries/illnesses is continuously expanding with an increasingly active and aging population. The use of bone replacements for bone fractures, removal of bone, or the use of supports for weakened bone requires that the artificial bone replacement form a strong joint or bone with natural bone to insure the integrity of the structure. Bone is able to grow into adjacent structure, particularly where the adjacent structures are porous and compatible with the bone. However, not only must the bone be able to grow into a porous structure, but there must be bonding in a form which allows for a strong bond between the natural ingrown bone and the prosthetic device.
The key requirement for bony fixation of prosthetic implants is that bone grows onto and/or into the implant""s surface. A number of studies have shown that calcium phosphate coatings, such as biological apatite, on Cobalt Chrome (Coxe2x80x94Cr) and Titanium (Ti)-alloy implants foster more rapid bony apposition than the bare surfaced alloys alone.
Biological apatite Ca10(PO4)6(OH)2 is one of the major compounds occurring in human bones and teeth. A synthetic form of this mineral, hydroxyapatite (HA) is very similar to the natural occurring apatite. This similarity between synthetic HA and naturally occurring apatite has led scientists to pursue the use of HA with dental and orthopedic implants. Coating with HA or other crystalline calcium phosphate produces an implant that readily integrates with surrounding bone and tissue after being implanted.
Some of the first dental and orthopedic implants attempting to employ synthetic apatite were completely formed from sintered or plasma sprayed HA.
Plasma spraying is one process known for coating metallic implants with HA. During this process, a stream of mixed gases passes through a high temperature electric arc that ionizes the gases into a plasma flame. Thereafter, crystalline HA feedstock powder is fed into the stream and then impinged in a molten state onto the outer surface of the implant. The spray adheres to the surface and forms a relatively thin coating of ceramic HA.
HA coated implants exhibit the advantages of both purely metallic implants and purely HA implants. As such, these implants are strong, and bone tissue tends to form a strong bone interface with the surface of the coating and thus promote biocompatibility and osseointegration. Unfortunately, plasma spraying results in several important disadvantages.
Plasma spraying exposes HA to extremely high temperatures that, in turn, induce unwanted changes in morphology and chemical composition. These changes pose particular problems. In particular, it is known that highly crystalline HA has an in vitro stability that is much higher than non-crystalline HA. HA feedstock of a good quality does have a completely crystalline form before it is sprayed. The temperatures associated with plasma spraying, though, cause the HA to partially transform from its pure and crystalline form to one having a much less crystalline structure. This non-crystalline form of HA is commonly referred to as amorphous calcium phosphate (ACP). During plasma spraying, crystalline HA feedstock is also partially converted into other crystalline compounds, such a tri-calcium phosphate (TCP including xcex1-TCP and xcex2-TCP), tetracalcium phosphate (TTCP), and calcium oxide (CaO). Collectively, these impurities may be referred to as crystalline soluble phases because their solubility in aqueous solutions is substantially higher than that of crystalline HA. Thus, a process for low temperature deposition of crystalline HA was desired.
Crystalline calcium phosphate coatings are preferably produced in a low temperature one or multi-step process which provides for a strong adherent uniform thin coating of crystalline hydroxyapatite on a substrate surface, where the coating has long needles or whiskers, which appear to induce bone ingrowth and strong bonding between natural bone and the coating via bone ingrowth and opposition on a pore comprising implant.
The coatings are found to have a high hydroxyapatite Ca10(PO4)6(OH)2 surface area because of the fibrous hydroxyapatite crystals. The surface area will generally range from about 1-25 m2/cm2 of area. The coatings may be as thin as about 2 xcexcm, preferably being at least about 5 xcexcm (xcexcm=microns), and more preferably at least about 10 xcexcm, and may range to 40 xcexcm thick or greater, depending upon need. Usually, a relatively thin coating will be employed to avoid thick brittle ceramic interfaces between the substrate and the ductile bone. The process taught in U.S. Pat. Nos. 5,164,187 and 5,188,670, the teachings of which are incorporated herein by reference, may produce such coatings.
The single crystals or whiskers, which are produced by the method of U.S. Pat. No. 5,164,187, will generally range from about 0.01 microns to 20 microns in diameter and about 1 micron to 40 microns in length. The composition will usually be substantially homogenous (xe2x89xa795%), mineralogically pure i.e., highly crystalline (same crystal structure) (xe2x89xa790%) and substantially homogenous morphologically, generally varying by no more than xc2x120% from the average of each dimension.
The crystalline hydroxyapatite has a net positive charge at physiologic pH which attracts charged proteins, such as collagen or other exogenous or endogenous proteins, which may serve as growth factors, chemoattractants, and the like. Thus, the coating may provide for the presence of such products on the surface of the hydroxyapatite. The exceptionally high surface of this coating presents orders of magnitude more binding surface than the uncoated implant or the conventional calcium phosphate coatings. Specifically, it has been found that plasma sprayed HA coatings would not bind to a solution or suspension of antibiotic.
The calcium phosphate coatings may be applied to solid surfaces, porous surfaces, etched surfaces, or any other type of surface. Because the coating is applied in a liquid medium which is able to penetrate channels, pores, indentations and other structural features, a uniform coating can be obtained which can coat substantially the entire surface, without leaving exposed areas. The subject process finds particular application with devices involving fine bead layers, where the beads will be two or more layers, requiring that at least about two layers of the beads be penetrated and coated with the hydroxyapatite or its analog. Thus, penetrations are achieved in a porous substrate, such as is used in prosthesis devices, of at least about 0.5 mm, more usually at least about 1 mm.
It is an object of the invention to provide a versatile and simple method of applying therapeutic agents to a calcium phosphate surface found by precipitation prior to implantation of a coated implant.
It is yet another object of the invention to provide a simple and fast method of providing a calcium phosphate coated surface with doses of water-soluble antibiotics prior to implantation of the implant.
These and other objects are achieved by a method where applying the therapeutic agent, especially an antibiotic, to the implant comprising coating the implant with preferably at least two layers of crystalline hydroxyapatite by precipitating the hydroxyapatite or calcium phosphate from solutions. The implant is then dried and packaged. In a preferred embodiment, immediately prior to implantation, the therapeutic agent or antibiotic is added to sterile deionized water or sterile water for injection and the implant is removed from the package and at least the hydroxyapatite or calcium phosphate surface thereof is immersed in the solution.
Alternatively, the antibiotic solution or suspension can be incorporated into the dried coating prior to packaging. The surgeon can then use the as supplied implant or add an additional coating of antibiotic to the HA antibiotic coated portion of the implant.
When applied in the operating room, the therapeutic solution may be pipetted into the calcium phosphate surface. The water and therapeutic agents may be added to the dried coating drop wise. The implant is then implanted in its wetted state. Alternately, the method for providing a therapeutic agent to an implant site includes providing the packaged implant coated with crystalline calcium phosphate or crystalline hydroxyapatite and the therapeutic agent by the same process as described above prior to packaging. If done in the operating room immediately prior to implantation, the calcium phosphate or hydroxyapatite coated implant is removed from the package and coated with an aqueous solution containing the therapeutic agent such as an antibiotic or a bone morphogenic protein. This can be done by immersing the calcium phosphate or hydroxyapatite coated implant into an aqueous solution of a therapeutic agent such as, for example, an antibiotic or bone growth stimulator such as bone morphogenic protein. Alternately, the aqueous solution may be pipetted or even poured over the surface. The implant may be either implanted in the bone canal in its wet condition or allowed to dry in air prior to implantation. The therapeutic agents, such as an antibiotic, may be either dissolved in the water to form the aqueous solution or may be suspended in the water to form the aqueous mixture that is placed on the calcium phosphate hydroxyapatite coating.
Useful antibiotics for use in this method are cefamandole, tobramycin, vancomycin, penicillin, cephalosporin C, cephalexin, cefaclor, cefamandole, ciprofloxacin and bisphosphonates.